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J. Biol. Chem., Vol. 279, Issue 25, 26645-26653, June 18, 2004

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AHNAK-mediated Activation of Phospholipase C-1 through Protein Kinase C^*

In Hye Lee, Je Ok You¶, Kwon Soo Ha¶, Duk Soo Bae||, Pann-Ghill Suh**, Sue Goo Rhee, and Yun Soo Bae

From the Division of Molecular Life Sciences, Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea, the ^¶Department of Biochemistry, Kangwon National University, Chuncheon, Kangwondo 200-701, Korea, the ^||Department of Obstetrics and Gynecology, Samsung Medical Center, SungKyunKwan University, Seoul 135-230, Korea, the ^**Department of Life Science, POSTECH, Pohang 790-784, Korea, and the Laboratory of Cell Signaling, NHLBI, National Institutes of Health, Bethesda, Maryland 20852

We have recently shown that phospholipase C- (PLC-) is activated by the central repeated units (CRUs) of the AHNAK protein in the presence of arachidonic acid. Here we demonstrate that four central repeated units (4 CRUs) of AHNAK act as a scaffolding motif networking PLC- and PKC-. Specifically, 4 CRUs of AHNAK bind and activate PKC-, which in turn stimulates the release of arachidonic acid near where PLC-1 is localized. Moreover, 4 CRUs of AHNAK interacted with PLC- and the concerted action of 4 CRUs with arachidonic acid stimulated PLC- activity. Stimulation of NIH3T3 cells expressing 4 CRUs of AHNAK with phorbol 12-myristate 13-acetate resulted in the increased generation of total inositol phosphates (IP_T) and mobilization of the intracellular calcium. Phorbol 12-myristate 13-acetate-dependent generation of IP_T was completely blocked in NIH3T3 cells depleted of PLC-1 by RNA interference. Furthermore, bradykinin, which normally stimulated the PLC- isozyme resulting in the generation of a monophasic IP_T within 30 s in NIH3T3 cells, led to a biphasic pattern for generation of IP_T in NIH3T3 cells expressing 4 CRUs of AHNAK. The secondary activation of PLC is likely because of the scaffolding activity of AHNAK, which is consistent with the role of 4 CRUs as a molecular linker between PLC- and PKC-.

Received for publication, October 21, 2003 , and in revised form, March 18, 2004.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^* This work was supported in part by the Korea Science and Engineering Foundation (KOSEF) through the Center for Cell Signaling Research at Ewha Womans University, a grant from the Molecular Medicine Research Program, 21C Frontier Functional Proteomics Project FPR02A7-32-110 (to Y. S. B.) from the Ministry of Science and Technology, Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea Grant HMP-00-GN-01-0001 (to Y. S. B.), and Korea Research Foundation Grant KRF-2002-042-200066 (to D. S. B.).

Recipient of a BK21 scholarship.

To whom correspondence should be addressed: Division of Molecular Life Sciences, Center for Cell Signaling Research, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Korea. Tel.: 82-2-3277-2729; Fax: 82-2-3277-3760; E-mail: baeys{at}ewha.ac.kr.

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